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WO2003101466A1 - Composition contenant du glycoside de rubrobusarine - Google Patents

Composition contenant du glycoside de rubrobusarine Download PDF

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Publication number
WO2003101466A1
WO2003101466A1 PCT/JP2003/006875 JP0306875W WO03101466A1 WO 2003101466 A1 WO2003101466 A1 WO 2003101466A1 JP 0306875 W JP0306875 W JP 0306875W WO 03101466 A1 WO03101466 A1 WO 03101466A1
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Prior art keywords
rubrofusarin
glycoside
intracellular
composition according
concentration
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PCT/JP2003/006875
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Japanese (ja)
Inventor
Sumio Asami
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Suntory Ltd
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Suntory Ltd
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Priority to US10/516,288 priority Critical patent/US20060110474A1/en
Priority to EP03733206A priority patent/EP1552838A4/fr
Publication of WO2003101466A1 publication Critical patent/WO2003101466A1/fr
Anticipated expiration legal-status Critical
Priority to US11/984,931 priority patent/US20080182803A1/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/30—Foods or foodstuffs containing additives; Preparation or treatment thereof containing carbohydrate syrups; containing sugars; containing sugar alcohols, e.g. xylitol; containing starch hydrolysates, e.g. dextrin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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    • A23L33/17—Amino acids, peptides or proteins
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    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/482—Cassia, e.g. golden shower tree
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L21/00—Marmalades, jams, jellies or the like; Products from apiculture; Preparation or treatment thereof
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    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to a composition for oral ingestion that contains rubrofusarin glycoside as an active ingredient and can increase the concentration of dartathione in vivo.
  • Conventional technology contains rubrofusarin glycoside as an active ingredient and can increase the concentration of dartathione in vivo.
  • Dartathion a tripeptide consisting of glutamic acid, cysteine, and glycine, is a multifunctional biological component that is contained in cells at a high concentration of 1 to 1 OmM.
  • daryuthione plays an important role in the elimination of hydrogen peroxide and lipid peroxide as a substrate for glutathione peroxidase. It is involved in detoxification and metabolism as a substrate for one of the enzymes, glutathione-S-transferase. It is also used as a substrate for glutathione dehydrogenase for the reactivation (reduction) of ascorbic acid oxidized in vivo.
  • Oral ingestion of daltathion directly contributes to the increase of dalatathion in living tissues because it is decomposed and no increase in blood concentration of daluthion is observed even when a high dose of daluthion is ingested. Not known (Eur. J. Clin. Pharmaco. 43, 667, 1 992).
  • W094 / 12527 discloses that the r-L-pyrodal mil-L cysteine acyl derivative promotes the biosynthesis of endogenous dalbut thione, which is an oxidative tissue disorder.
  • it is effective for treating various diseases caused by deficiency or deficiency of dartathione such as a pathological condition involving a disorder caused by excessive free radicals.
  • Examples of the diseases mentioned here include alcohol consumption, xenobiotics, radiation damage, intracellular oxidation due to liver disease, poisoning with medicines and other compounds, poisoning with heavy metals, brain physiology Aging (for example, Parkinson's disease, which is a decline in the brain due to loss of memory and learning ability, or a decrease in the concentration of dartation associated with changes in defense mechanisms against bio-oxidants), and acute and chronic neurological diseases (Acute medical conditions include cerebral seizures, hypoglycemia and epileptic seizures as acute ischemic conditions, and chronic medical conditions include amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's chorea) However, there are dysfunctions in the immune system, especially reduced immunity against cancer, infertility, especially male infertility. Furthermore, it is disclosed that the above compounds are also suitable for ischemia / reperfusion injury of organs which are the main cause of free radicals.
  • Japanese Patent Laid-Open No. 1-26516 describes an L-Daltamil-L- It is disclosed that a compound that increases the concentration of dartathione is effective in the treatment and prevention of various diseases including cataract, liver disease and kidney disease.
  • S-lower fatty acid dartathione derivatives are disclosed as anti-inflammatory, anti-allergic, hepatic disorder inhibitors (W091 / 12262, 091/16337), and sugar-containing dalbutione derivatives are disclosed as liver protecting agents (Japanese Patent Laid-Open No. 9-25292). It has been shown that increasing the amount of tissue dull thione is effective in treating and preventing a wide range of diseases. With regard to dartathione ester derivatives, the following findings have been reported to have a protective effect against tissue cell damage as listed below. In other words, butioninsulfoximine-induced cataract (Pro. Natl. Acad. Sci.
  • the present invention is different from the method for supplying precursor amino acids used in the biosynthesis of daryuthione.
  • the present invention provides a composition for oral intake that can promote intracellular biosynthesis of dalbutin.
  • FIG. 1 is a graph showing that rubration concentrations in human hepatocyte-derived HepG2 cells increase over time by rubrofusarin glycoside, compared with silibinin.
  • Fig. 2 is a graph showing a dose-dependent increase in the concentration of dalbutthione in human hepatocyte-derived HepG2 cells compared to 3-naphthoflavone and silibinin due to rubrofusarin glycosides.
  • FIG. 3 is a graph showing the protective effect of rubrofusaline glycoside on the killing of human hepatocyte-derived HepG2 cells against t-butyl hydroperoxide in comparison with 3 naphthoflavone used as a positive control.
  • FIG. 4 is a graph showing that rubrofusarin glycoside and cystine which is a precursor amino acid of daryuthione synergistically contribute to an increase in daryuthione concentration in human hepatocyte-derived HepG2 cells.
  • Fig. 5 is a graph showing that oral administration of a concentrate containing rubrofusarin glycosides has an inhibitory effect on the decrease in dartathione level in liver tissue and the increase in lipid peroxidation (TBARS value) due to restraint stress. .
  • A Liver dull thione content
  • Figure 6 shows that oral administration of a concentrate containing rubrofusarin glycosides has an inhibitory effect on the reduction of brain dalbution levels and increased lipid peroxidation (TBARS) due to restraint stress. It is a graph.
  • A Brain tissue dartathione content
  • B Brain tissue TBARS value.
  • the present inventor conducted a search for an active ingredient that increases the ability to synthesize daryuthione in cells suitable for the above-mentioned purpose using materials having a wide range of dietary experience, and found that an effective ingredient is present in the ketchei extract. We identified that this active ingredient is rubrofusarin glycoside.
  • synthetic compounds such as / 3-naphthoflavone (J. Biol. Chem. (1998) 273, 14683) and silymarin (Planta Med. 55, 420, 1989), Sanohydroxybutene (Toxicol. Appl.
  • Kecameshi is the seed of Cassia obtusifolia, a member of the legume family, and has been roasted and drunk for a long time.
  • Kekmeishi has the following effects: “cleansing the liver, revealing eyes, using water, passing stool” In particular, “blue-blind, eye-skinned skin, red-and-white membrane, redness and pain in the eyes, and things that don't stop with tears coming out, and if you take it for a long time, it will benefit luminescence (eye light)” Cited to the scriptures and introduced that it is an effective herbal medicine for the eyes. It is also referred to as “Ophthalmic Drugs” in the section of “Medical Pharmacy for Clinical Medicine” (Medical and Pharmaceutical Publishing).
  • the present invention relates to a rubrofusarin glycoside for maintaining a high level of in vivo (tissue, intracellular) dalbutione thiophene glycoside, to which rubrofusarin glycoside is added as an active ingredient. It is a composition for oral intake containing this.
  • Ruprofufalin glycoside has the following formula:
  • sugar component A examples include gentiobiose and glucose.
  • a preferred sugar component is gentiobiose, in which case the rubrofusarin glycoside is rubrofusarin gentiobioside.
  • Rubrofusarin glycosides are contained in extracts from natural products, and examples of natural products that can be used as raw materials include Kassmeia (Cass ia ob tus i fo lia) and Cassia (Cass ia occ i dent al is ;
  • Rubrofusarin glycoside may be an active ingredient of the composition of the present invention as a pure substance, or may be an active ingredient of the composition in the form of an extract from a natural product.
  • a preferred natural product as a raw material is Kecamesi, but any material containing rubrofusarin glycosides is not limited to Kecamesi, but can also be used in the same way.
  • the ruburofusarin glycosides are treated according to the purpose such as extraction operation from the raw material such as Kecameshi dried seeds containing rubrofusarin glycosides.
  • a concentrated composition containing a predetermined amount may be used.
  • the solvent used to extract rubrofusarin glycosides from natural products is water or an organic solvent.
  • organic solvents include alcohols such as ethanol and methanol, esters such as ethyl acetate, ketones such as acetone, methyl
  • Ethers such as ethyl ether can be used. Two or more of these water or organic solvents may be used in combination, but when aiming for food or drink, it is appropriate to use water or an aqueous ethanol solution.
  • An example of the preparation of an extract concentrate containing the rubrofusarin glycoside of the present invention using Ketchei as a raw material is as follows.
  • the method and conditions should be adopted so that the concentrate contains as much of the rubrofusarin glycoside as possible.
  • a concentrate containing 1 to 30% by weight of luprofusalin glycoside per concentrate (dry solid) is desirable.
  • the heating temperature is preferably 50 ° C to 95 ° C.
  • the amount of solvent added for extraction is, for example, 3 to 10 times the amount of the raw material.
  • the content and purity of rubrofusarin glycoside in the filtrate obtained by extraction is about 2.2% for 70% ethanol extraction and 1.1% for thermal extraction (see Table 1).
  • an adsorption resin such as Diaion HP 20 (manufactured by Mitsubishi Chemical Corporation) and activated carbon, which are widely used for industrial purposes, can be used.
  • the extraction filtrate is directly applied to the resin, and when extraction is performed using an aqueous ethanol solution as the solvent, the concentration is reduced under reduced pressure, etc. • Contact the extract with the resin.
  • a decrease in the ethanol concentration is preferable in order to sufficiently adsorb rubrofusarin glycosides.
  • the ethanol concentration is preferably reduced to 20% or less.
  • the concentration of ingredients can be set according to each purpose, and a method suitable for that can be selected.
  • an ethanol solution can be used for elution by a method such as stepwise or concentration gradient.
  • a non-limiting example is 20% ethanol wash Z80% ethanol. Elution, 30% ethanol washing, Z60% ethanol elution, etc. are possible.
  • the eluate thus obtained can be concentrated or dried into powder by ordinary methods such as vacuum concentration and freeze drying.
  • a dry powdered product can be produced using conventional dextrin, polymer starch hydrolyzate, or polymer peptide as an excipient. .
  • rubrofusarin glycosides eg, high-purity rubrofusaringen thiobioside
  • column chromatography, high performance liquid chromatography, liquid-liquid partition chromatography using the above extract concentrate is used.
  • the desired purity can be obtained by treatment according to a conventional method such as:
  • the solvent system is 0.1% trifluoroacetic acid-containing aqueous solution of acetonitrile containing 10% -80% (acetonitrile concentration) gradient elution, resulting in a reproducible peak with good resolution. Since the active ingredient is eluted, if this is collected, rubrofusarin glycoside (eg, rubrofusarin gentiobioside) can be obtained as almost a single ingredient.
  • Example 2 In order to monitor the purity and yield of rubrofusarin during the above extraction / purification process, the measurement method described in Example 2 can be used.
  • rubrofusarin glycoside is a component that contains 3 mg or more of raw cereals per lg. It is considered to be highly safe because it has been drunk considerably and has been used orally. These findings should be reflected in the content setting of the rubrofusarin glycoside of the present invention. Therefore, the composition of the present invention has no substantial upper limit on the amount of rubrofusarin glycoside which is an active ingredient, but preferably 0.5% by weight or more to 30% by weight, more preferably 1% Add more than 15% to less than 15% by weight. '
  • rubrofusa phosphorus glycoside As a pure substance or as a concentrate from a natural raw material, a composition for oral consumption that can be easily ingested in an effective amount can be provided.
  • Rubrofusarin glycosides are sufficiently stable to pH, moisture, oxidation, light, etc. and exhibit some bitterness. Therefore, the composition for oral ingestion according to the present invention can be used in various forms such as foods and drinks, seasonings, alcoholic beverages, functional foods, and pharmaceuticals depending on purposes. It is possible to alleviate or maintain the level of dalbution in cells / tissues / organs caused by oxidative stress. For example, maintaining liver function, brain function, visual function, immune function, etc.
  • compositions include a solid form, a semi-fluid form, and a fluid form.
  • solid foods include biscuits, sheets, tablets such as tablets and capsules, and general foods and health foods in the form of granular powders.
  • Semi-fluid foods include pastes, jellies, and gels.
  • Liquid foods include juices, soft drinks, teas, drinks, and other general and health foods. .
  • composition of the present invention contains an amount of rubrofusarin glycoside that functions to increase the intracellular concentration of dalbutthione, and is not particularly limited except that it is safe to ingest. .
  • rubrofusarin glycoside may be included as a single active ingredient, or alternatively, a precursor for intracellular dalbutione biosynthesis, especially nutritional science.
  • L-cystine ZL-cystine (however, it is known that oral administration of a significant amount of free L-cystine is toxic, Am. J. C li n. Nu tr. 50, 1401, 1989) and L-methionine can be added to achieve a synergistic effect of increasing the function of darumathione.
  • a synergistic effect is a composition containing both of these at the same time compared to the sum of the effect of increasing the intracellular dalbution concentration of a composition containing only rubrofusarin glycoside and the effect of a composition containing only a precursor. This means that this action is larger.
  • precursors include L-cystine ZL-cystine, L-methionine-rich egg white and egg membranes, animal products such as milk whey (milk), proteins such as soybeans and plant-derived yeasts, Peptides processed and prepared from them, and addition of L-cystine and L-methionine approved as food additives can be mentioned.
  • These precursors or foods containing them in high content are preferably blended in a composition of about 0.1 to 10% by weight per solid as L-cysteine content.
  • vitamin C ascorbic acid
  • the composition for ingestion is effective for alleviating physical problems related to lifestyle habits as described above.
  • the usage may be before, after, during, or between meals, but preferably between meals, and the frequency of use is preferably taken 3 times daily, but is not limited to this. It doesn't matter.
  • the tablet shown in Example 10 is designed according to such a setting. Those who specifically recommend the use of this composition for ingestion are those who are concerned about redness of their eyes or vision loss, those who are concerned about senile cataracts as they age, those who are concerned about smoking disorders, smoking Examples include people who are concerned about UV rays, including sunlight, skin with aging, wrinkles, and spots.
  • Example 1 Identification of active ingredients
  • a 70% (v Z v) ethanol extract of Kemeshi is placed on a Diaion HP20 adsorption column and washed with a 30% ethanol solution and then extracted with a 70% ethanol solution. Further purification was performed by liquid chromatography, and the active ingredient of the present invention was identified.
  • Reversed phase high-performance liquid chromatography uses a Develos il ODS-HG5 column (6 X 100mm, manufactured by Nomura Chemical) with a 3D monitor, and 10% of the above extract concentrate (89 mg / ml aqueous solution). Elution was carried out under the conditions of a linear concentration gradient (12 minutes) containing 25% to 40% acetonitrile with 0.1% trifluoroacetic acid, and the fractions collected at intervals of 15 seconds were dried under reduced pressure. Later, it was dissolved in 20 ⁇ 1 dimethyl sulfoxide (DMS0).
  • DMS0 dimethyl sulfoxide
  • the culture solution is removed and washed once with phosphate buffered saline (PBS), and then 25 ⁇ 1 of 0.25 mM monochlorobimane-containing PBS solution is added and C0 2 Incubator ( 3 The sample was left in c) for 45 minutes, and after returning to room temperature, 75 ⁇ 1 distilled water was added and homogenized.
  • the fluorescence intensity of the fluorescent substance produced by the reaction between the black-and-white biman and dartathione was measured under the conditions of 355 nm and Z460 nm, and the fluctuation of intracellular dartathione content was observed. As a result, a dose-dependent fraction was observed, and a fraction showing a strong activity of increasing intracellular dartathione was found.
  • Example 3 Decrease in content of rubrofusarin glycoside with roasting
  • extraction was performed at room temperature for 1 day, and a filtrate was obtained by filtration through a filter (dry weight: 14.5 g, rubrofusarin glycoside 3.0% by weight).
  • the filtrate was concentrated under reduced pressure to make a final solution of 500 ml of 20% (v / v) ethanol, then placed on a Diaion ⁇ 0 adsorption column (100m 1) and washed with non-adsorbed components with 100 ml of 20% ethanol solution ( Dry weight of non-adsorbed material: 10.8g).
  • Table 2 summarizes the dry weight and the weight percent of rubrofusarin glycosides.
  • HepG2 cells derived from human hepatocytes were used to examine the time-dependent inducibility of rubu-fusalin glycosides to the intracellular dartathione concentration.
  • the operating method is the same as in Example 1. I.e. HepG2 cells were dispensed and fixed at 2.5 x 10 4 cells (100 1) per well of the microplate, and then 25 ⁇ 1 of an evaluation sample diluted to a predetermined concentration was added to RPMI1640 medium. The culture was performed over time until 12, 24 and 48 hours.
  • the concentrate of the present invention prepared according to the method of Example 4 (containing 10.2% (w / w) of rubus mouth fusarin geniobioside) and glutathione in tissues in rats for comparison purposes.
  • hepG2 cells derived from human hepatocytes we examined the dose-dependence of lupus-oralin glycosides on intracellular dartathione concentration.
  • the operating method is in accordance with Example 5.
  • 2.5 x 10 4 cells (100 1) per well of a microplate were dispensed and fixed in HepG2 cells, and 25 1 of a concentrate serially diluted to a predetermined concentration with RPMI1640 medium was added to 25 1 (activity)
  • the final concentration is 0 to 20 xM in terms of rubrofusarin gentiobioside, which is a component, and after further incubation for 48 hours, the intracellular dartathione concentration is not added to the sample.
  • HepG2 cells derived from human hepatocytes were used to show resistance to peroxide compounds by giving rubrofusarin glycosides.
  • the operating method is in accordance with Example 5. That is, after HepG2 cells were dispensed and settled at 2.5 x 10 4 cells (100 n 1) per well of the microplate, the final concentration was 10 / M in terms of rubrofusaringentiobioside in RPMI1640 medium.
  • hepG2 cells derived from human hepatocytes we observed a synergistic effect of rubrofusarin glycoside, which has an activity to increase intracellular dartathione, and a precursor for dartathione biosynthesis.
  • the procedure is the same as in Example 1, but the RPMI1640 medium does not contain L-cystine because it contains a sufficient amount of the precursor L-cystine and does not meet the purpose of this example.
  • -MEM with 10% serum
  • a medium was prepared and used. That is, after HepG2 cells were dispensed and fixed at 2.5 x 10 4 cells (100 a 1) per well of the microphone plate, The medium was changed to the D-MEM medium (100 1) containing no L-cystine.
  • TBARS dartathione and lipid peroxide (thiobarbituric acid reactant: TBARS) in each organ were measured. More specifically, a 9 (w / v) volume of ice-cold homogenization solution (154 mM KC1, 5 mM DTPA, 10 mM KPi buffer) was removed per weight of each organ stored at 80 ° C. , pH 6.8) and a homogenate was prepared using Fiscotron (manufactured by Nisshin Medical Science Instrument Co., Ltd.), and the TBARS value was determined according to the method of Ohkawa et al. Anal. Biochem. 95.
  • Example 1 0 Composition of concentrate-containing tablet
  • Extract concentrate 50.0 22.2 1 1 .1

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Abstract

Compte tenu de l'amélioration de la capacité de synthèse du glutathion dans les cellules en tant que moyen différent du procédé consistant à fournir un acide aminé précurseur utilisé dans la biosynthèse du glutathion ou en tant que moyen à utiliser avec le procédé susmentionné, l'invention porte sur une composition orale contenant un ingrédient actif autre qu'un acide aminé précurseur, ce qui permet de promouvoir la biosynthèse du glutathion dans les cellules afin de maintenir un niveau de glutathion élevé in vivo (dans les tissus ou dans les cellules). En d'autres termes, l'invention concerne une composition orale permettant d'élever la concentration de glutathion dans les cellules vitales contenant au moins un glycoside de rubrofusarine dans une quantité suffisamment efficace pour élever la concentration de glutathion in vivo.
PCT/JP2003/006875 2002-05-31 2003-05-30 Composition contenant du glycoside de rubrobusarine Ceased WO2003101466A1 (fr)

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US10/516,288 US20060110474A1 (en) 2002-05-31 2003-05-30 Rubrofusarin glycoside-containing composition
EP03733206A EP1552838A4 (fr) 2002-05-31 2003-05-30 Composition contenant du glycoside de rubrobusarine
US11/984,931 US20080182803A1 (en) 2002-05-31 2007-11-26 Rubrofusarin glycoside-containing composition

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JP2002-160176 2002-05-31
JP2002160176A JP4520089B2 (ja) 2002-05-31 2002-05-31 ルブロフサリン配糖体含有組成物

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JP2006206509A (ja) * 2005-01-28 2006-08-10 Ｔｏｗａ Ｃｏｒｐｏｒａｔｉｏｎ 株式会社 マカ抽出物の製造方法
JPWO2007004570A1 (ja) * 2005-06-30 2009-01-29 サントリー株式会社 持久力向上および／または抗疲労作用を有する組成物
GB2439925B (en) * 2006-07-10 2009-01-14 Chongqing Inst Of Ecological M Anti-obesity plant extract comprising anthraquinones and its method of preparation
US8602961B2 (en) 2008-05-15 2013-12-10 Lifewave Products Llc Apparatus and method of stimulating elevation of glutathione levels in a subject
US20120189563A1 (en) * 2009-09-30 2012-07-26 Shiseido Company, Ltd. Oral composition for alleviating ultraviolet irradiation-induced damage
CN102093449B (zh) * 2011-01-06 2014-01-22 刘斌 一种自决明子中分离制备红镰霉素龙胆二糖苷的方法
CN103196847B (zh) * 2013-03-21 2015-09-30 湖南大学 重金属胁迫下白腐真菌胞内活性巯基化合物的定量检测方法
CN107200760A (zh) * 2016-04-06 2017-09-26 长沙博海生物科技有限公司 一种高纯度红镰霉素-6-O-β-龙胆二糖苷的制备方法
KR102121915B1 (ko) * 2018-09-03 2020-06-11 한국과학기술연구원 결명 새싹 유래 나프토파이론 유도체를 포함하는 신경세포 보호용 조성물

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EP1552838A4 (fr) 2007-12-12
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